EP2482867A1 - Reins bioartificiels améliorés - Google Patents

Reins bioartificiels améliorés

Info

Publication number
EP2482867A1
EP2482867A1 EP10820925A EP10820925A EP2482867A1 EP 2482867 A1 EP2482867 A1 EP 2482867A1 EP 10820925 A EP10820925 A EP 10820925A EP 10820925 A EP10820925 A EP 10820925A EP 2482867 A1 EP2482867 A1 EP 2482867A1
Authority
EP
European Patent Office
Prior art keywords
unit
reabsorption
semi
bioartificial kidney
membrane
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP10820925A
Other languages
German (de)
English (en)
Inventor
Jackie Y. Ying
Edwin Pei Yong Chow
Jeremy C.M. Teo
Karl Schumacher
Jeremy Ming Hock Loh
Rosa Yue Qi
Qunya Ong
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Agency for Science Technology and Research Singapore
Original Assignee
Agency for Science Technology and Research Singapore
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Agency for Science Technology and Research Singapore filed Critical Agency for Science Technology and Research Singapore
Publication of EP2482867A1 publication Critical patent/EP2482867A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D63/00—Apparatus in general for separation processes using semi-permeable membranes
    • B01D63/08—Flat membrane modules
    • B01D63/082—Flat membrane modules comprising a stack of flat membranes
    • B01D63/084—Flat membrane modules comprising a stack of flat membranes at least one flow duct intersecting the membranes
    • B01D63/085—Flat membrane modules comprising a stack of flat membranes at least one flow duct intersecting the membranes specially adapted for two fluids in mass exchange flow
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02—Prostheses implantable into the body
    • A61F2/022—Artificial gland structures using bioreactors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/14—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/34—Filtering material out of the blood by passing it through a membrane, i.e. hemofiltration or diafiltration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/34—Filtering material out of the blood by passing it through a membrane, i.e. hemofiltration or diafiltration
    • A61M1/3403—Regulation parameters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/34—Filtering material out of the blood by passing it through a membrane, i.e. hemofiltration or diafiltration
    • A61M1/3403—Regulation parameters
    • A61M1/341—Regulation parameters by measuring the filtrate rate or volume
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D61/00—Processes of separation using semi-permeable membranes, e.g. dialysis, osmosis or ultrafiltration; Apparatus, accessories or auxiliary operations specially adapted therefor
    • B01D61/14—Ultrafiltration; Microfiltration
    • B01D61/145—Ultrafiltration
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D69/00—Semi-permeable membranes for separation processes or apparatus characterised by their form, structure or properties; Manufacturing processes specially adapted therefor
    • B01D69/14—Dynamic membranes
    • B01D69/141—Heterogeneous membranes, e.g. containing dispersed material; Mixed matrix membranes
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M23/00—Constructional details, e.g. recesses, hinges
    • C12M23/54—Constructional details, e.g. recesses, hinges hand portable
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M25/00—Means for supporting, enclosing or fixing the microorganisms, e.g. immunocoatings
    • C12M25/02—Membranes; Filters
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M29/00—Means for introduction, extraction or recirculation of materials, e.g. pumps
    • C12M29/04—Filters; Permeable or porous membranes or plates, e.g. dialysis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2205/00—General characteristics of the apparatus
    • A61M2205/33—Controlling, regulating or measuring
    • A61M2205/3331—Pressure; Flow
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2209/00—Ancillary equipment
    • A61M2209/08—Supports for equipment
    • A61M2209/088—Supports for equipment on the body
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D2319/00—Membrane assemblies within one housing
    • B01D2319/02—Elements in series
    • B01D2319/025—Permeate series
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D2319/00—Membrane assemblies within one housing
    • B01D2319/06—Use of membranes of different materials or properties within one module

Definitions

  • the present invention generally relates to improved bioartificial kidneys.
  • kidney disease chronic kidney disease
  • ESRD end stage renal failure
  • the ultrafiltrate that is produced flows across the tubule of the nephron, whereby biological reabsorption of certain molecules back into the circulatory system occurs.
  • the selective biological reabsorption of water, glucose and ions is performed by an epithelium cell layer that lines the tubules.
  • Molecules that are not reabsorbed are removed from the body as urine. Failure of the mechanical filtration or biological reabsorption function, provided by the glomerulus or tubules respectively, would result in a plethora of clinical complications.
  • hemodialysis treatment has been employed to artificially replace the mechanical filtration function of glomerulus.
  • Polymeric membranes with open interconnected pores, in the form of hollow fibers, are used in these dialyzers where they function as a sieving medium with carefully controlled pore sizes.
  • This treatment is generally administered to patients 3—4 times a week for 2—4 h/treatment.
  • prolonged intermittent treatment may be detrimental due to hemodynamic instability as a result of large shift of solutes and fluids over a short period of time.
  • Dialyzers used for hemodialysis are therefore incomplete artificial kidney assist devices.
  • Bioartificial kidneys containing functional kidney cells have been developed to provide the cellular functions of tubules.
  • BAKs Bioartificial kidneys
  • PES polyethersulfone
  • HPTCs primary human kidney proximal tubule cells
  • the present invention generally relates to bioartificial kidneys, and in certain embodiments to improved bioartificial kidneys that are portable and/or wearable by a user.
  • the subject matter of the present invention involves, in some cases, interrelated products, alternative solutions to a particular problem, and/or a plurality of different uses of one or more systems and/or articles.
  • a bioartificial kidney comprises a blood side configured to be placed in fluid communication with a blood supply and a permeate side, the blood side and the permeate side separated from each other by at least one semi-permeable membrane, wherein at least one semi-permeable membrane has a non-tubular configuration and has seeded thereon a plurality of human renal proximal tubule cells.
  • the plurality of human renal proximal tubule cells form substantially a monolayer of cells on at least a portion of at least one semi-permeable membrane having a non-tubular configuration.
  • the plurality of human renal proximal tubule cells form substantially a monolayer of cells on substantially the entirety of at least one side of the semi-permeable membrane of the reabsorption unit.
  • the bioartificial kidney comprises a plurality of semipermeable membranes, at least one semi-permeable membrane being essentially free of adhered cells.
  • the at least one semi-permeable membrane being essentially free of adhered cells is positioned in an ultrafiltration unit having an inlet in fluid communication with the blood supply, and wherein the at least one semi-permeable membrane having a non-tubular configuration and having seeded thereon a monolayer of human renal proximal tubule cells is positioned in a reabsorption unit in fluid
  • the ultrafiltration unit and the reabsorption unit are contained in a single housing.
  • the ultrafiltration unit is contained in a first housing and the reabsorption unit is contained in a separate housing.
  • a bioartificial kidney comprises an ultrafiltration unit comprising a blood side configured to be placed in fluid communication with a blood supply and a permeate side, the blood side and the permeate side separated from each other by a semi-permeable membrane.
  • the bioartificial kidney further comprises a reabsorption unit in fluid communication with the permeate side of the ultrafiltration unit, the reabsorption unit comprising a retentate side and a permeate side, the retentate side and the permeate side of the reabsorption unit being separated from each other by a semi-permeable membrane, wherein the semi-permeable membrane of the reabsorption unit has a non-tubular configuration and has seeded thereon a plurality of human renal proximal tubule cells.
  • the plurality of human renal proximal tubule cells form substantially a monolayer of cells on at least a portion of the semi-permeable membrane of the reabsorption unit.
  • the plurality of human renal proximal tubule cells form substantially a monolayer of cells on substantially the entirety of at least one side of the semi-permeable membrane of the reabsorption unit:
  • the semi-permeable membrane of the reabsorption unit comprises polysulfpne-Fullcure.
  • a bioartificial kidney comprises an ultrafiltration unit comprising a blood side configured to be placed in fluid communication with a blood supply and a permeate side, the blood side and the permeate side separated from each other by a semi-permeable membrane.
  • the bioartificial kidney further comprises a reabsorption unit in fluid communication with the permeate side of the ultrafiltration unit, the reabsorption unit comprising a retentate side and a permeate side, the retentate side and the permeate side of the reabsorption unit separated from each other by a semi-permeable membrane, wherein the semi-permeable membrane of the reabsorption unit comprises polysulfone-Fullcure.
  • the semi-permeable membrane of the reabsorption unit has a non-tubular configuration.
  • At least a portion of the semi-permeable membrane of the reabsorption unit has seeded thereon substantially a monolayer of human renal proximal tubule cells
  • the plurality of human renal proximal tubule cells form substantially a monolayer of cells on substantially the entirety of at least one side of the semi-permeable membrane of the reabsorption unit.
  • a method of filtering blood in an bioartificial kidney comprises flowing blood from a patient into a blood side of an ultrafiltration unit if the bioartificial kidney that is configured to be placed in fluid communication with the blood supply, passing at least a portion of a fluid component of the blood through a semi-permeable membrane to form a permeate on a permeate side, of the ultrafiltration unit, flowing at least a portion of the permeate into a retentate side of a reabsorption unit of the bioartificial kidney, passing at least a portion of the permeate from the ultrafiltration unit through a non-tubular semi-permeable membrane of the reabsorption unit that has seeded thereon human renal proximal tubule cells to form a reabsorbate in the retentate side of the reabsorption unit, and returning at least a portion of the reabsorbate to the patient.
  • the human renal proximal tubule cells form substantially a monolayer on at least a portion of the semi-permeable membrane of the reabsorption unit. In other embodiments, the human renal proximal tubule cells form substantially a monolayer of cells on substantially the entirety of at least one side of the semi-permeable membrane of the reabsorption unit.
  • the bioartificial kidney is capable of filtering the blood supply of the patient continuously for at least 1 day without substantial fouling.
  • the ultrafiltration unit and the reabsorption unit are contained in a single housing.
  • the ultrafiltration unit is contained in a first housing and the reabsorption unit is contained in a separate housing.
  • the semi-permeable membrane of the reabsorption unit is substantially flat.
  • the semi-permeable membrane of the ultrafiltration unit is substantially flat.
  • the bioartificial kidney is configured to be portable. In still other embodiments, the bioartificial kidney is configured to be wearable by a user.
  • the semi-permeable membrane of the ultrafiltration unit has a molecular weight cut-off of less than 10 kDa.
  • the semi-permeable membrane of the ultrafiltration unit has a thickness between 50 microns and 500 microns.
  • the semi-permeable membrane of the reabsorption unit has a thickness between 10 microns and 200 microns.
  • any of the bioartificial kidneys or methods above further comprise a membrane support layer in the reabsorption unit configured to provide support to the semi-permeable membrane of the reabsorption unit to resist applied pressure.
  • any of the bioartificial kidneys or methods above further comprise a membrane support layer in the ultrafiltration unit configured to provide support to the semi-permeable membrane of the ultrafiltration unit to resist applied pressure. 10 000377
  • the permeate side of the ultrafiltration unit contains channels having a smaller cross-sectional area than channels in the blood side of the ultrafiltration unit.
  • FIG. 1 shows an exploded view of a miniaturized flat-bed BAK comprising the ultrafiltration and reabsorption units, according to an embodiment
  • FIG. 2 shows a schematic of fluid flow within the miniaturized flat-bed BAK, according to an embodiment
  • FIG. 3 shows an ultrafiltration chamber containing two polycarbonate flat plates that sandwich a customized microporous polymeric membrane, according to an embodiment
  • FIGs. 4A-4D show various graphs, according to an embodiment: (FIG. 4A) a graph showing ultrafiltration rates; (FIG. 4B) a graph showing albumin sieving coefficient; (FIG. 4C) a graph showing urea clearance; and (FIG. 4D) a graph showing creatinine clearance of (a) 20wt%PSFC150, (A) 20wt%PSFC150-5wt%MPC, (x) 20wt%PSFC200-5wt%MPS, and ( ⁇ ) 10 kDa Pall OmegaTM membranes, according to certain embodiments; FIGs. 5A-5E show schematics of retentate chambers (FIGs. 5A and 5B) and various graphs illustrating device performance (FIGs. 5C-5E), according to an embodiment;
  • FIGs. 6A-6E show schematics of ultrafiltration units (FIGs. 6A and 6B) and various graphs illustrating device performance (FIGs. 6C-6E), according to an embodiment, according to an embodiment;
  • FIGs. 7A-7E show a photograph of a flat-bed BA (FIG. 7A) and various graphs illustrating device performance (FIGs. 7B-7E), according to an embodiment
  • FIG. 8 shows an exploded view of a reabsorption unit chamber, according to an embodiment, that comprises two polycarbonate flat plates that sandwich a customized microporous polymeric membrane;
  • FIG. 9 shows a patient wearing a wearable bioartificial kidney
  • FIG. 10 is a photographic image showing immuno fluorescent staining of HPTCs seeded onto 10wt%PSFC200 membrane, according to an embodiment - immunostaining was performed after 2 weeks of cultivation, and ZO-1 (greyscale, top) as well as AQP-1 (red, bottom) were detected - nuclei were counterstained with DAPI (blue, bottom);
  • FIG. 11 is a graph showing measured transmembrane resistance for renal epithelial cells seeded on (A) 10wt%PSFC200 and ( ⁇ ) PET membranes, according to an embodiment.
  • FIG. 12A-12C show various graphs illustrating device performance, according to an embodiment.
  • the present invention generally relates to bioartificial kidneys, and in certain embodiments to improved bioartificial kidneys that are portable and/or wearable by a user.
  • the B A s may comprise an ultrafiltration unit and a reabsorption unit.
  • the ultrafiltration unit and the reabsorption unit may be contained in a single housing, which may be partitioned, in certain cases, into a first rigid walled compartment containing the ultrafiltration unit and a second rigid walled compartment containing the reabsorption unit.
  • the single housing which may contain only a single rigid walled compartment containing both membrane(s) forming an ultrafiltration section (ultrafiltration unit) and membrane(s) forming a reabsorption unit.
  • the ultrafiltration unit and the reabsorption unit may each be contained in a physically separate, independently movable housing, where the housings are connected in fluid communication with each other.
  • the reabsorption unit generally contains a reabsorption membrane at least a portion of which having a plurality of renal proximal tubule cells disposed thereon, where the renal proximal tubule cells selectively allow solutes to pass through the reabsorption membrane.
  • the plurality of human renal proximal tubule cells forms substantially a monolayer of cells on at least a portion of the semipermeable membrane of the reabsorption unit, and in certain such embodiments the plurality of human renal proximal tubule cells forms substantially a monolayer of cells on substantially the entirety of at least one side of the semi-permeable membrane of the reabsorption unit,
  • the reabsorption unit may be configured as a substantially flat device (e.g.
  • disk- or plate-like with a thickness substantially less than a width, length or diameter of the device which can impart advantageous properties such as improved maintenance of the renal proximal tubule cell layer and more facile monitoring of the renal proximal tubule cell layer, as well as, in certain embodiments, greater portability and wearability.
  • FIG. 1 shows an exploded view of an embodiment of a flat-bed BAK 100 containing a housing 102 having a first volumetric compartment 104 comprising an ultrafiltration unit 110 and a second volumetric compartment 106 comprising a reabsorption unit 120, which is described in more detail below.
  • the compartment comprising the ultrafiltration unit contains a retentate chamber 11 1 , an ultrafiltration membrane 112, an ultrafiltration membrane support layer 113, and a permeate chamber 114.
  • the reabsorption unit contains an apical chamber 121 , a monolayer of cells on the apical facing side of a reabsorption membrane 122, a reabsorption membrane support layer 123, and a basolateral chamber 124.
  • Each of the two volumetric compartments comprise polymeric membranes, which are designed to replace the physiological functions of the native glomerulus and tubules.
  • the membranes used for the ultrafiltration and reabsorption units may be optimized for solute selectivity and renal epithelial cell support, respectively.
  • FIG. 2A shows a cross-sectional schematic depicting the operation of the embodiment of the BAK of FIG. 1.
  • the BAK comprises an inlet 200 that is in fluid - Si - communication with the circulation system of a subject. Blood flows into the ultrafiltration unit 210 through the inlet.
  • the ultrafiltration unit comprises an
  • ultrafiltration membrane 211 through which fluid, but not cells, can pass.
  • a hemodialysis membrane may be used.
  • a hemofiltration membrane may be used.
  • Permeate refers to the fluid that has been passed through the membrane.
  • Retentate refers to the portion of the blood that does not cross the membrane.
  • the blood flows through the inlet into the retentate chamber (i.e., the retentate side) 212, where the blood contacts the ultrafiltration membrane. Fluid from the blood passes through the ultrafiltration membrane into the permeate chamber 213 (i.e., the permeate side).
  • the retentate and permeate then flow into the reabsorption unit 220.
  • the reabsorption unit comprises an apical chamber (i.e., the retentate side) 221 into which the permeate from the ultrafiltration unit flows and a basolateral chamber (i.e., the permeate side) 222 into which the retentate from the ultrafiltration unit flows.
  • the apical chamber and the basolateral chamber are separated by a membrane 223 seeded with renal epithelial cells 224.
  • the renal epithelial cells are seeded only on the side of the membrane that is in fluid communication with the apical chamber.
  • the permeate from the ultrafiltration unit flows into the apical chamber where it contacts the renal epithelial cells.
  • a portion of the fluid from the permeate passes through the membrane seeded with renal epithelial cells into the basolateral chamber (i.e., selected solutes are biologically reabsorbed by the membrane to elute on the basolateral side of the reabsorption unit and are mixed with the retentate from the ultrafiltration unit and recirculated).
  • This fluid is herein referred to as the "reabsorbate.”
  • the residual permeate containing solutes not reabsorbed by the cells flows out of the B AK and into a waste container.
  • the combined retentate and reabsorbate flows out of the B AK and back into the circulation system of a subject.
  • the ultrafiltration unit and the reabsorption unit may be combined in a single volumetric compartment having rigid bounding walls, as opposed to the two compartment partitioned housing as illustrated in FIGs. 1 and 2A.
  • the single compartment configuration may have the rigid partition layer 230 removed forming a first, upstream region of the compartment where ultrafiltration occurs and a second, downstream region where reabsorption occurs.
  • the ultrafiltration unit and the reabsorption unit may be contained in T/SG2010/000377
  • FIG. 2B the ultrafiltration unit 250 and the reabsorption unit 260 are contained in separate housings 251, 261.
  • the ultrafiltration unit 300 may comprise two plates 310, 320 (e.g., polymer plates, such as polycarbonate) with an ultrafiltration membrane 330 and an ultrafiltration membrane support layer 340 sandwiched in between to separate the retentate chamber 350 and the permeate chamber 360 (FIG. 3).
  • the membranes described herein i.e., the ultrafiltration membrane and reabsorption membrane
  • the plates may have a serpentine flow-field layout 370 that increases the length of the flow path thereby increasing the efficiency of ultrafiltration of blood across the membrane.
  • the channels 371 in the permeate chamber may each have a smaller cross-sectional dimension transverse to the flow direction than the channels in the retentate chamber in order to increase the flow resistance of the device so as to generate a higher trans-membrane pressure (TMP).
  • TMP trans-membrane pressure
  • the distortion can, in some embodiments, be alleviated by the incorporation of microchannels 371 into the serpentine flow field design to act as an additional support for the membrane against flexural failure of the membrane.
  • a macroporous membrane may be placed beneath the polymeric membrane to provide additional mechanical support.
  • microchannels may be excluded from the retentate chamber so as to minimize the possibility of blood coagulation along the channel walls, which could result in the blockage of the channels and ultimately failure of the device.
  • the fluid flow resistance within the BAK may be controlled. For example, in some embodiments, the fluid flow resistance may be increased by increasing the number of microchannels in the plate adjacent to the permeate chamber.
  • the permeate chamber channel may be sub-divided into smaller channels. These smaller channels may provide increased support to the polymeric membranes, without restricting the flow of the filtrate.
  • a reservoir may be incorporated at the inlet to reduce the energy associated with the feed fluid, thereby preventing puncture of the membrane.
  • a double o-ring design may be used to provide an essentially leak-proof ultrafiltration unit.
  • the retentate chamber and the permeate chamber may be configured (e.g., molded) such they may be seated together with proper alignment.
  • the plates forming the two chambers may have a combination of depressions and protrusions 380 on the inside surfaces, where the depressions and protrusions align so as to align the two plates when fitted together.
  • the ultrafiltration unit may be sealed using one or more o-rings, gaskets or other sealing arrangements to make the unit essentially leak-proof.
  • blood may be pumped along the surface of the membrane in the ultrafiltration unit by tangential flow.
  • Solutes having a size above a threshold value generally do not pass through the pores of the ultrafiltration membrane and may be retained in the retentate chamber.
  • the tangential flow can minimize fouling of the membrane by maintaining flow of the solutes in the retentate.
  • the TMP allows sieving of smaller solutes through the pores of the membrane and into the permeate chamber (see FIG. 2A, for example).
  • the ultrafiltration membrane is able to remove uremic substances (e.g., urea and creatinine) from blood selectively, while preventing leakage of useful proteins (e.g., albumin).
  • the pore size of the ultrafiltration membrane may be used to control the membrane selectivity.
  • the membranes may have a total protein permeability of less than 2%, less than 1%, less than 0.5%, less than 0.2%, or less than 0.1%.
  • the pore size of the membrane may be chosen such that the membrane may have a predetermined molecular weight cut-off value.
  • the membrane may have a molecular weight cutoff (MWCO) that is less than 1/6 of the molecular weight of the smallest substance to be retained.
  • MWCO molecular weight cutoff
  • the MWCO of the membrane would be chosen to be less than about 10 kDa.
  • the MWCO of the membrane may be less than 50 kDa, less than 20 kDa, less than 10 kDa, less than 5 kDa, or less than 2 kDa.
  • the membrane may be non-tubular in configuration.
  • the membrane may be in the form of a substantially flat sheet.
  • the ultrafiltration membrane may be fabricated from a polymeric material.
  • polymers such as polysulfone and FullcureTM (Objet Geometries, Inc.) may be used. Additional examples of polymers that can be used to form structures described herein include but are not limited to: polyvinyl alcohol, polyvinylbutryl, polyvinylpyridyl, polyvinyl pyrrolidone, polyvinyl acetate, acrylonitrile butadiene styrene (ABS), ethylene-propylene rubbers (EPDM), EPR, chlorinated polyethylene (CPE), ethelynebisacrylamide (EBA), acrylates (e.g., alkyl acrylates, glycol acrylates, polyglycol acrylates, ethylene ethyl acrylate (EEA)), hydrogenated nitrile butadiene rubber (HNBR), natural rubber, nitrile butadiene rubber (NBR), certain fluoropol
  • HNBR
  • chlorosulfonyl rubber flourinated poly(arylene ether) (FPAE)
  • FPAE flourinated poly(arylene ether)
  • polyether ketones polysulfones
  • polyether imides diepoxides
  • diisocyanates diisothiocyanates
  • polymers that can be used to form structures described herein include but are not limited to: polyamines (e.g., poly(ethylene imine) and polypropylene imine (PPI)); polyamides (e.g., polyamide (Nylon), poly(e- caprolactam) (Nylon 6) , poly(hexamethylene adipamide) (Nylon 66)), polyimides (e.g., polyimide, polynitrile, and poly(pyromellitimide-l,4-diphenyl ether) (Kapton)); vinyl polymers (e.g., polyacrylamide, poly(2 -vinyl pyridine), polyvinylpyrrolidone), poly(methylcyanoacrylate), poly (ethylcyanoacry
  • polyamines e.g., poly(ethylene imine) and polypropylene imine (PPI)
  • polyamides e.g., polyamide (Nylon), poly(e- caprolactam) (Nylon 6)
  • poly(ethylene oxide) PEO
  • poly(propylene oxide) PPO
  • poly(tetramethylene oxide) PTMO
  • vinylidene polymers e.g., polyisobutylene, poly(methyl styrene),
  • polymethylmethacrylate PMMA
  • polyaramides e.g., poly(imino-l,3-phenylene iminoisophthaloyl) and poIy(imino-l,4-phenylene iminoterephthaloyl)
  • polyheteroaromatic compounds e.g., polybenzimidazole (PBI), polybenzobisoxazole (PBO) and polybenzobisthiazole (PBT)
  • polyheterocyclic compounds e.g., polypyrrole
  • polyurethanes phenolic polymers (e.g., phenol-formaldehyde); polyalkynes (e.g., poly acetylene); polydienes (e.g., 1 ,2- polybutadiene, cis or trans- 1,4-polybutadiene); polysiloxanes (e.g.,
  • PDMS poly(dimethylsiloxane)
  • PDES poly(diethylsiloxane)
  • PDPS polydiphenylsiloxane
  • PMPS polymethylphenylsiloxane
  • inorganic polymers e.g., polyphosphazene, polyphosphonate, polysilanes, polysilazanes. Additional polymers that may be used are described in International Patent Application Serial No.
  • the membrane may be treated with or comprise one or more compositions that impart anti-fouling properties to the membrane.
  • the membrane may comprise 2-methacryloyloxyethyl phosphorylcholine, 3- methylacryloyloxy propyltrimethoxysilane, or other non-fouling compositions.
  • the ultrafiltration membrane may be selected to yield desired performance properties. For example, decreasing the membrane thickness may allow more efficient ultrafiltration by shortening the distance that fluid must flow from the retentate chamber to the permeate chamber.
  • the thickness of the ultrafiltration membrane may be, in some embodiments, between 50 microns and 500 microns, between 50 microns and 400 microns, between 50 microns and 300 microns, between 50 microns and 200 microns, between 100 microns and 500 microns, between 100 microns and 400 microns, or between 200 microns and 400 microns.
  • decreasing the membrane thickness also may decrease the mechanical strength of the membrane.
  • a macroporous membrane support layer may be placed between the ultrafiltration membrane and the permeate chamber, as shown in FIGs. 1 and 3.
  • the support layer may be macroporous relative to the
  • ultrafiltration membrane and/or reabsorption membrane are provided above.
  • the reabsorption unit may be in fluid communication with the ultrafiltration unit.
  • the permeate and retentate obtained at the end of the ultrafiltration unit can be flowed into the apical chamber and the basolateral chamber, respectively (FIG. 2A, 2B).
  • the permeate would come into contact with the human proximal tubule cell epithelium layer, and the human proximal tubule cells would perform their biological functions in regulating the reabsorption and metabolism of important substances such as glucose, water and ions.
  • Fluid and solutes from the permeate would then be transported across the human proximal tubule cell layer and reabsorption unit membrane into the basolateral chamber.
  • the combined retentate and reabsorbate in the basolateral chamber may be then returned to the patient.
  • FIG. 8 shows an exploded view of one embodiment of a reabsorption unit.
  • the unit 800 comprises an apical chamber 810 and a basolateral chamber 820.
  • the unit also comprises a thin 100- ⁇ reabsorption membrane 830 supported on a membrane support layer 840.
  • the reabsorption membrane is used as a substrate for renal proximal tubule cells.
  • a double o-ring design 850 is used to provide an essentially leakproof
  • the reabsorption unit membrane may have a thickness of between 10 microns and 200 microns, between 50 microns and 200 microns, or between 75 microns and 150 microns.
  • the reabsorption membrane may be fabricated from a polymeric material.
  • polymers such as polysulfone and FullcureTM (Objet Geometries, Inc.) may be used.
  • renal proximal tubule cells seeded on membranes fabricated from polysulfone and FullcureTM may exhibit improved growth and/or morphology.
  • polymers that can be used to form structures described herein include but are not limited to: polyvinyl alcohol, polyvinylbutryl, polyvinylpyridyl, polyvinyl pyrrolidone, polyvinyl acetate, acrylonitrile butadiene styrene (ABS), ethylene-propylene rubbers (EPDM), EPR, chlorinated polyethylene (CPE), ethelynebisacrylamide (EBA), acrylates (e.g., alkyl acrylates, glycol acrylates, polyglycol acrylates, ethylene ethyl acrylate (EEA)), hydrogenated nitrile butadiene rubber (HNBR), natural rubber, nitrile butadiene rubber (NBR), certain fluoropolymers, silicone rubber, polyisoprene, ethylene vinyl acetate (EVA), chlorosulfonyl rubber, flourinated poly(arylene ether) (FPAE), polyether ketones, poly(ary
  • polymers that can be used to form structures described herein include but are not limited to: polyamines (e.g., poly(ethylene imine) and polypropylene imine (PPI)); polyamides (e.g., polyamide (Nylon), poly(e- caprolactam) (Nylon 6) , poly(hexamethylene adipamide) (Nylon 66)), polyimides (e.g., polyimide, polynitrile, and poly(pyromellitimide-l,4-diphenyl ether) (Kapton)); vinyl polymers (e.g., polyacrylamide, poly(2-vinyl pyridine), polyvinylpyrrolidone), poly(methylcyanoacrylate), poly (ethylcyanoacry late),
  • polyamines e.g., poly(ethylene imine) and polypropylene imine (PPI)
  • polyamides e.g., polyamide (Nylon), poly(e- caprolactam) (Nylon 6)
  • poly(ethylene oxide) PEO
  • poly(propylene oxide) PPO
  • poly(tetramethylene oxide) PTMO
  • vinylidene polymers e.g., polyisobutylene, poly(methyl styrene),
  • poly(methylmethacrylate) PMMA
  • poly(vinylidene fluoride) polyaramides
  • poly(imino-l,3 -phenyl ene iminoisophthaloyl) and poly(imino-l,4-phenylene iminoterephthaloyl) polyaramides
  • polyheteroaromatic compounds e.g., polybenzimidazole (PBI), polybenzobisoxazole (PBO) and polybenzobisthiazole (PBT)
  • polyheterocyclic compounds e.g., polypyrrole
  • polyurethanes phenolic polymers (e.g., phenol-formaldehyde); polyalkynes (e.g., poly acetylene); polydienes (e.g., 1,2- polybutadiene, cis or trans- 1 ,4-polybutadiene); polysiloxanes (e.g.,
  • PDMS poly(dimethylsiloxane)
  • PDES poly(diethylsiloxane)
  • PDPS polydiphenylsiloxane
  • PMPS polymethylphenylsiloxane
  • inorganic polymers e.g., polyphosphazene, polyphosphonate, polysilanes, polysilazanes. Additional polymers that may be used are described in International Patent Application Serial No.
  • a reabsorption unit membrane support layer may be included between reabsorption unit membrane and the basolateral chamber to provide mechanical support for the reabsorption unit membrane and to prevent sagging of the reabsorption unit membrane due to differential pressure across the apical chamber and the basolateral chamber.
  • the apical chamber and basolateral chamber may be configured (e.g., molded) such they may be seated together with proper alignment in a similar fashion as described above for the retantate and permeate chambers of the ultrafiltration unit.
  • the reabsorption unit may be sealed using one or more o-rings, gaskets or other sealing arrangements to provide an essentially leak- proof seal.
  • the one or more o-rings may aid in preventing outside microbial infection of the proximal tubule cells.
  • the membrane used in the reabsorption unit should be able to facilitate the attachment, proliferation, and support of the proximal tubule cell epithelium layer.
  • certain polymers such as polysulfone and
  • FullcureTM may be chosen that allow improved performance of renal proximal tubule cells.
  • the reabsorption unit membrane may have molecular weight cutoff of less than 10 kDa, less than 20 kDa, less than 30 kDa, less than 40 kDa, less than 50 kDa, less than 60 kDa, or less than 80 kDa.
  • the cell layer on the reabsorption unit membrane may comprise renal proximal tubule cells.
  • the renal proximal tubule cells may be obtained from human subjects or other mammalian subjects.
  • the cells form a continuous layer on the reabsorption unit membrane such that permeate cannot pass through the reabsorption unit membrane without passing through the renal proximal tubule cell layer.
  • the cells form a confluent epithelium on the membrane.
  • the paracellular spaces may be sealed by tight junctions.
  • the cells form a monolayer on the surface of the reabsorption membrane.
  • the renal proximal tubule cells may be co-cultured with other cells.
  • the renal proximal tubule cells may be co-cultured with renal cell types (e.g. distal tubule cells, collecting duct cells, podocytes and renal fibroblasts) or endothelial cells.
  • renal cell types e.g. distal tubule cells, collecting duct cells, podocytes and renal fibroblasts
  • endothelial cells e.g., endothelial cells
  • the performance of renal proximal tubule cells e.g., the ability to reabsorb substances
  • one or more agents can be used to promote formation and/or maintenance of renal proximal tubule cell morphology and confluence.
  • bone morphogenic protein 7 BMP-7
  • the one or more agents may be released in controlled fashion from within the BAK.
  • the one or more agents may be produced within the renal tubule cells.
  • the BAK may be configured to be portable.
  • the BAK may be a wearable device, i.e., a device worn on a user (i.e., a subject or patient).
  • a patient 900 may wear a BAK 910 that is connected to the patient's circulatory system by an inlet tube 920 and an outlet tube 930.
  • a waste bag 940 for collection of waste from the BAK through waste tube 950.
  • a wearable BAK presents the opportunity for a subject to have continuous blood filtration over an extended period of time.
  • the B AK may be capable of substantially continuous blood filtration for a period of at least 1 hour, at least 10 hours, at least 1 day, at least 2 days, at least 4 days, at least 1 week, at least 2 weeks, at least 1 month, at least 2 months, at least 3 months, at least 6 months, or even at least 1 year.
  • the BAK is a capable of substantially continuous blood filtration without substantial fouling compromising acceptable performance.
  • the channel surfaces and/or membranes in the BAK may be substantially non-fouling during operation of the BAK.
  • the BAK may filter blood at a rate of at least 50 mL per hour, at least 100 mL per hour, at least 200 mL per hour, at least 300 mL per hour, or at least 500 mL per hour.
  • the BAK may comprise one or more pumps for assisting fluid flow within the device.
  • the pump may be battery powered, for example.
  • This example demonstrates the performance of an embodiment of an inventive BAK.
  • PSFC polysulfone/FullcureTM
  • MPC 2-methacryloyloxyethyl phosphorylcholine
  • MPS 3- methacryloyloxy propyltrimethoxysilane
  • membranes with an optimum micro structure could be obtained with or without post-treatment (Table 1).
  • PS polysulfone
  • FC Fullcure
  • MPC MPC
  • MPS MPS
  • membranes with an optimum micro structure could be obtained with or without post-treatment (Table 1).
  • These membranes had a MWCO of ⁇ 30 kDa, and were hence impermeable to albumin, while providing high permeability to water and other small molecules. They had a hydraulic permeability to water (ultrafiltration rate) of ⁇ 10-100 ml/(h-m 2 -mmHg), and a diffusive permeability to creatinine and urea of > O.SxlO ⁇ cm/s.
  • PSFC membranes (especially 20wt%PSFC200-5wt%MPS) offered superior ultrafiltration rates, and urea and creatinine clearances.
  • a liquid pore stabilizer such as glycerol or polyethylene glycol.
  • FIGs. 5A and 5B show a permeate chamber 500 containing a serpentine channel layout 510, where the
  • microchannels 511 in the chamber of FIG. 5A are larger than the microchannels 512 in the chamber of FIG. 5B.
  • the device resistance increased hydraulic flow resistance, which in turn promoted ultrafiltration.
  • the albumin sieving values obtained were similar, but the ultrafiltration rates (FIG. 5C), and urea and creatinine clearances (FIG. 5D) were higher using a device with more microchannels (V2) as compared to a device with fewer microchannels (VI).
  • FIG. 5E albumin sieving
  • FIG. 6A The ultrafiltration characteristics of 20wt%PSFC200-5wt%MPS membranes of two different thicknesses, 300 ⁇ (FIG. 6A, 600) and 100 ⁇ (FIG. 6B, 610), were compared. As the thinner membrane 610 has less mechanical strength, it was placed on top of a macroporous membrane support layer 620 (FIG. 6B).
  • FIGs. 6A and 6B Cross-sectionsiof the two setups are schematically presented in FIGs. 6A and 6B, which show the membranes within the housing 605.
  • FIGs. 6C-6E show the ultrafiltration test results using the two different setups. The effects of membrane thickness were assessed by replacing (FIG. 6A) the 300- ⁇ PSFC membrane (Tl) with (FIG.
  • the best membrane from the in vitro ultrafiltration study (20wt%PSFC200- 5wt%MPS) was selected for hemofiltration performance comparison with commercial membranes, such as Pall membranes of different MWCO (10 kDa and 30 kDa), in a setup 700 shown in FIG. 7A.
  • Fresh rabbit blood was pumped at 200 ml/min through the ultrafiltration unit for 4 h to simulate clinical dialysis duration. Filtration rate, albumin sieving coefficient, and urea and creatinine clearances were measured (FIG. 7).
  • FIG. 7 A Rabbit blood was used as the feed solution and perfused at 300 rrnVmin into ultrafiltration unit of the flat-bed BAK.
  • FIG. 7B Ultrafiltration rate, (FIG.
  • the membrane used in the reabsorption unit was configured to be able to facilitate the attachment,, roliferation, and support of a well-differentiated HPTC epithelium layer.
  • PS/polyvinylpyrrolidone (PVP) and PES/PVP membranes found in most commercial hemodialyzers were not able to perform such a function.
  • HPTCs were seeded on PSFC membranes, and the number of live cells was determined by using the 3-(4,5-dimethyltWazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H- tetrazolium (MTS) assay (FIG. 9).
  • a control study was conducted to determine the cultivation duration needed to attain a renal epithelium layer on PSFC membranes. This was performed by measuring the transepithelial electric resistance across the apical and basolateral side of cell-seeded membranes using an epithelial voltohmmeter (EVOM2, World Precision Instruments, Sarasota, PL). Commercial polyethylene terephthalate (PET) membranes were used as a control. Resistance was measured everyday after initial cell seeding density of
  • Cell-seeded PSFC membranes cut to size, were seeded with HPTC cells and cultivated for 5 days. The cell-seeded membranes were then placed in the reabsorption unit for reabsorption studies.
  • the apical chamber was perfused with growth factor and fetal bovine serum (FBS)-free cell culture medium that has been spiked with inulin, urea and creatinine. This condition simulated the clearance of the uremic solutes by the glomerulus into the tubules of the nephron.
  • the basolateral chamber was perfused at a similar rate of 1 ml/min as the apical chamber, with growth factor and FBS-free cell culture medium.
  • Renal epithelial cell covered PSFC membranes seeded initially at 50,000/cm , were placed into the flat-bed BAK after 3 days of cultivation.
  • Serum-free cell culture medium without growth factors, spiked with inulin, urea and creatinine, was perfused into the apical chamber of the reabsorption unit.
  • the basolateral side of the reabsorption unit was perfused with serum- free cell culture medium.
  • the concentrations of (FIG. 12 A) inulin, (FIG. 12B) urea and (FIG. 12C) creatinine in the ( ⁇ ) apical and (w) basolateral chambers of the bioreactor were measured.
  • Table 1 Composition of precursors used in the preparation of PSFC-based ultrafiltration membranes.
  • the phrase "at least one,” in reference to a list of one or more elements, should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements.
  • This definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase "at least one" refers, whether related or unrelated to those elements specifically identified.
  • At least one of A and B can refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc.

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Abstract

La présente invention concerne, de façon générale, des reins bioartificiels améliorés (BAK), et dans certains modes de réalisation, des reins bioartificiels améliorés portatifs et/ou portables par un utilisateur. Dans certains modes de réalisation, lesdits BAK peuvent comprendre une unité d'ultrafiltration et une unité de réabsorption. L'unité de réabsorption peut comporter une membrane de réabsorption comprenant une couche de cellules de tubules proximaux de rein disposée à sa surface, lesdites cellules des tubules proximaux de rein permettant un passage sélectif des solutés à travers la membrane de réabsorption. Dans certains modes de réalisation, au moins l'unité de réabsorption peut prendre la forme d'un dispositif de filtration se présentant sous la forme d'une plaque essentiellement plane, ce qui peut lui conférer des propriétés intéressantes, telles qu'un entretien plus aisé de la couche de cellules de tubules proximaux de rein, un suivi facilité de la couche de cellules de tubules proximaux de rein, ainsi qu'une section moindre, ce qui va faciliter le port du dispositif.
EP10820925A 2009-10-02 2010-10-04 Reins bioartificiels améliorés Withdrawn EP2482867A1 (fr)

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